The use of cannabis and cannabinoids for medical purposes has been gaining increased interest in recent years. There is a growing body of evidence that cannabis may have a beneficial impact on clinical conditions such as pain (e.g. cancer pain, fibromyalgia related pain, neuropathic pain), inflammatory diseases (e.g. inflammatory bowel diseases, Crohn's disease, ulcerative colitis), posttraumatic stress disorder (PTSD), loss of appetite/anorexia, sleep disorders, symptoms of multiple sclerosis (MS), epilepsy, autism, schizophrenia, and other disorders. The principal active components of cannabis plant that modulate the human endocannabinoid system are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Similarly to the endocannabinoids, anandamide and 2-AG, THC can activate both CB1 and CB2 receptors exerting a wide variety of biological effects by mimicking these endocannabinoids. In contrast to THC, CBD has a relatively low affinity for CB1 and CB2 receptors. However, several groups have recently shown that CBD antagonizes cannabinoid agonists, indicating that CBD can interact with cannabinoid CB1 and CB2 receptors.
THC is a psychoactive substance that accounts for the therapeutic effect as well as some adverse events. THC effects include, antiemetic properties, mild to moderate analgesic effects, relaxation, alteration of visual, auditory, and olfactory senses, and fatigue. CBD, a major non-psychotropic constituent of cannabis, has multiple pharmacological actions, including anticonvulsant, anxiolytic, antipsychotic, antiemetic, sedative, anti-inflammatory, anti-epileptic, anti-oxidative and neuro-protective actions. Moreover, it is thought to alleviate the untoward psychotropic effects of THC. The multiple mechanism of action of CBD support its possible therapeutic effects in many diseases, e.g. MS, Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, nausea and cancer.
The rationale for using a combination of the two cannabinoids stems from the reports in the scientific literature that CBD could not only potentiate the therapeutic effects of THC, but also diminish the undesirable effects of THC, such as anxiety, panic, sedation, dysphonia and tachycardia. Additionally, co-administration of THC and CBD was reported to be safe with no tolerance, abuse or withdrawal effects. Therefore, a pharmaceutical dosage form that combines the two active cannabinoids and enables efficient delivery is most desirable.
There are only few cannabis-based drug products, which are either approved for marketing as drugs or are in their last stages of development, which are manufactured under more strict good manufacturing practice requirements for pharmaceuticals. The first cannabis-based medicine was Marinol®, a synthetic THC (dronabinol), formulated in sesame oil in oral soft gelatin capsules. It is indicated for treatment of cachexia in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to adequately respond to conventional antiemetic treatments. Among its drawbacks are poor bioavailability, high inter- and intra-subject variability, and other THC related side effects. Therefore, its compliance and use are relatively limited. Another currently marketed cannabinoids-based drug is Sativex®, initially indicated for symptomatic treatment in MS. It is a buccal spray formulated in ethanol, propylene glycol, and peppermint oil. It is administered onto the oromucosal surface and therefore claims to bypass the ‘first pass’ metabolism of cannabinoids associated with intestinal absorption. However, a number of adverse events experienced with Sativex limit its use. Sativex formulation contains excipients that following continuous use often lead to lesions, mouth ulcerations, pain and soreness of the oral mucosa. In such cases, the treatment has to be interrupted until complete healing of the oral mucosa occurs. In addition, the pharmacokinetic data of Sativex showed great intra and inter subject variability following single and repeated dosing. In terms of clinical practice, the highly variable and erratic pharmacokinetic profiles of this product leads to increased daily usage nearly by 3-fold, and compliance of patients to such frequent daily dosage is usually poor.
An optimal oral dosage form of cannabinoids is not yet available due to the substantial ‘first pass’ metabolic effect which limits the oral bioavailability of cannabinoids to 6% [1]. Currently, medical cannabis is administered primarily through smoking or, alternatively, consumed orally in the form of oil, cookies, chocolates, etc. The majority of these products are not standardized, i.e. cannabinoids composition and doses are uncontrolled, and demonstrate major disadvantages of poor bioavailability resulting in administration of very high cannabinoid doses and increased side effects, high dosing frequency, high variability, low patient compliance, and short product self-life due to formulation instability.
Certain gelatin-based formulations comprising active ingredients other than cannabinoids have been described in U.S. Pat. Nos. 5,387,415 [2], 5,902,606 [3] and 6,068,854 [4].